Project Summary Opioid use disorder (OUD) has grown to epidemic proportions over the past few decades, affecting millions of Americans and contributing to tens of thousands of deaths each year. While medication is a cornerstone for the treatment of OUD, current therapeutics act upon the mu opioid receptor (MOR) itself. MOR agonists have a high risk of misuse and so their administration must be tightly regulated, while MOR antagonists necessitate a supervised withdrawal period before the beginning of treatment. These requirements create significant barriers to access for people with OUD who seek treatment. An alternative strategy for the treatment of OUD is to target receptors other than MOR which mediate addiction. One such target is the serotonin 2C (5-HT2C) receptor, which exerts tonic inhibition over mesolimbic dopaminergic signaling, the pathway underlying the brain's reward response to stimuli such as drugs of abuse. Preclinical data has validated 5-HT2C agonism as an effective means for treating addiction to cocaine, alcohol, and nicotine. Though less extensively investigated, recent preclinical studies have supported the efficacy of 5-HT2C agonism against opioid addiction as well. In the course of our studies of metabolites of yohimbine natural products, we have designed and synthesized a lead compound exhibiting agonism of 5-HT2C. The objective of my proposal is the further development of a potent, biased, and selective small molecule 5- HT2C agonist followed by efficacy studies in animal models for opioid addiction. Synthesis of analogs of our lead compound will be guided by computational molecular docking and informed by in vitro functional assays for potency, bias, and selectivity, and top analogs will be advanced into pharmacokinetic and toxicity testing. Selected analogs will then be advanced into in vivo efficacy studies, using a drug-induced Conditioned Place Preference assay in mice. This research training plan encompasses medicinal chemistry, organic synthesis, computational modeling, chemical biology, neuroscience, and in vivo assay techniques. It will be carried out as part of a collaborative effort between the Northwestern University Department of Chemistry and the Feinberg School of Medicine Translational Neuropharmacology Program, with further support from outside collaborators.